(European) Consensus on the use Botulinum Toxin in ... ¤nemark... · PDF...
Transcript of (European) Consensus on the use Botulinum Toxin in ... ¤nemark... · PDF...
(European) Consensus on the use Botulinum Toxin in Children with CP
A. Sebastian Schroeder, Florian Heinen, Steffen Berweck
Hauner Children‘s Hospital, Ludwig-Maximilians-University Munich, GermanySpecialist Centre of Paediatric Neurology and Rehabilitation
www.munichultrasoundcourse.com iTunes U | Sono's Anatomy Blue Book Botulinumtoxin Red Book Botulinumtoxin App | iPhone | iPad
Freitag, 23. November 2012
Consensus framework for BoNT treatment in CP
1. The updated European Consensus 2009 on the use of Botulinum toxin for children with cerebral palsy. Heinen F, et al. Eur J Paediatr Neurol. 2010 Jan;14(1):45-66.
2. Botulinum toxin assessment, intervention and after-care for lower limb spasticity in children with cerebral palsy: international consensus statementLove et al. Eur. J. Neurol. 2010, 17 Suppl.
3. Botulinum toxin assessment, intervention and follow-up for pediatric upper limbhypertonicity: international consensus statementFehling et al. Eur. J. Neurol. 2010, 17 Suppl. 2
Botulinum toxin assessment, intervention and after-care for lowerlimb spasticity in children with cerebral palsy: internationalconsensus statement
S. C. Lovea, I. Novakb, M. Kentishc, K. Desloovered, F. Heinene, G. Molenaersf, S. O!Flahertyg
and H. K. Grahamh
aCentre for Musculoskeletal Studies, University of Western Australia, Princess Margaret Hospital, Western Australia; bCerebral Palsy
Institute, School of Medicine, University of Notre Dame Australia, Darlinghurst, Sydney, NSW; cQueensland Cerebral Palsy Health Service,
Department of Paediatric Rehabilitation, Royal Children!s Hospital, Brisbane, QLD, Australia; dDepartment of Rehabilitation Sciences,
KUL, Leuven, Belgium; ePaediatric Neurology & Developmental Medicine, Children!s Hospital University of Munich, Munich, Germany;fDepartment of Musculoskeletal Sciences, KUL, Leuven, Belgium; gRehabilitation Dept, Children!s Hospital at Westmead, Westmead, NSW,
Australia; and hUniversity of Melbourne, Department of Orthopaedics and Murdoch Children!s Research Institute, The Royal Children!s
Hospital, Parkville, Vic., Australia
Keywords:
botulinum neurotoxin A,cerebral palsy, equinus,gait, goal attainment,gross motor function,spasticity
Received 9 July 2009
Accepted 14 May 2010
Botulinum neurotoxin type-A (BoNT-A) has been used in association with otherinterventions in the management of spasticity in children with cerebral palsy (CP) foralmost two decades. This consensus statement is based on an extensive review of theliterature by an invited international committee. The use of BoNT-A in the lowerlimbs of children with spasticity caused by CP is reported using the AmericanAcademy of Neurology Classification of Evidence for therapeutic intervention. Ran-domized clinical trials have been grouped into five areas of management, and theoutcomes are presented as treatment recommendations. The assessment of childrenwith CP and evaluation of outcomes following injection of BoNT-A are complex, andtherefore, a range of measures and the involvement of a multidisciplinary team isrecommended. The committee concludes that injection of BoNT-A in children withCP is generally safe although systemic adverse events may occur, especially in childrenwith more physical limitations (GMFCS V). The recommended dose levels areintermediate between previous consensus statements. The committee further concludesthat injection of BoNT-A is e!ective in the management of lower limb spasticity inchildren with CP, and when combined with physiotherapy and the use of orthoses,these interventions may improve gait and goal attainment.
Introduction & objectives
Botulinum neurotoxin type-A (BoNT-A) has been usedin the management of spasticity in the lower limbs ofchildren with CP for more than 15 years, with the firstreports by Koman et al. from the United States in 1993[1] and Graham et al. in the United Kingdom in 1994[2]. The original indication, which remains the mostcommon today, was injection of the gastrocsoleus forthe correction of spastic equinus or improvement of
equinus gait (toe-walking). Since the first reports,indications have been extended to almost every majormuscle in the lower limb, with varying degrees of suc-cess and variable levels of evidence.
This international consensus statement reviews theevidence for the use of BoNT-A therapy in the lowerlimbs of children with spasticity caused by CP, formu-lates them into appropriate treatment recommendationsand identifies areas for future research based on gaps inthe literature. In addition, areas of clinical relevancewithout high levels of evidence have been reviewedincluding assessments, outcome measures, adjunctivetherapies, recommended doses, dilution, muscle locali-zation techniques and screening for adverse events. Asuggested management algorithm is also provided.
Correspondence: S. C. Love, Associate Professor, Manager Outpatient
Physiotherapy Services, Princess Margaret Hospital, GPO Box D184
Perth 6840, WA, Australia (tel.: +61 8 9340 8503; fax:
+61 8 93408597; e-mail: [email protected]).
! 2010 The Author(s)Journal compilation ! 2010 EFNS 9
European Journal of Neurology 2010, 17 (Suppl. 2): 9–37 doi:10.1111/j.1468-1331.2010.03126.x
Botulinum toxin assessment, intervention and follow-up forpaediatric upper limb hypertonicity: international consensusstatement
D. Fehlingsa, I. Novakb, S. Berweckc, B. Hoared, N. S. Stotte and R. N. RussofaBloorview Research Institute, Bloorview Kids Rehab, Department of Paediatrics, University of Toronto, Toronto, ON, Canada; bCerebral
Palsy Institute, School of Medicine, University of Notre Dame Australia, Darlinghurst, Sydney, New South Wales, Australia; cTreatment
Centre Vogtareuth, Specialist Centre for Paediatric Neurology, Paediatric Rehabilitation and Epilepsy for Children & Adolescents,
Vogtareuth, Germany; dVictorian Paediatric Rehabilitation Service, Monash Children!s, Southern Health, Clayton, Victoria, Australia;eDepartment of Surgery, The University of Auckland, Auckland, New Zealand; and fFlinders University School of Medicine, Flinders
University South Australia and Paediatric Rehabilitation Department, Women!s and Children!s Hospital, South Australia, Australia
Keywords:
assessment, botulinumtoxin A, children,hypertonicity,occupational therapy,spasticity, systematicreview, upper limb/extremity
Received 9 July 2009
Accepted 14 May 2010
The primary objective of this paper was to evaluate the published evidence of e!cacyand safety of botulinum neurotoxin (BoNT) injections in paediatric upper limbhypertonia (PULH). Secondary objectives included the provision of clinical context,based on evidence and expert opinion, in the areas of assessment, child and muscleselection, dosing, and adjunctive treatment. A multidisciplinary panel of authorssystematically reviewed, abstracted, and classified relevant literature. Recommenda-tions were based on the American Academy of Neurology (AAN) evidence classifi-cation. Following a literature search, 186 potential articles were screened for inclusion,and 15 of these met the criteria and were reviewed. Grade A evidence was found tosupport the use of BoNT to reach individualized therapeutic goals for PULH. There isgrade B evidence (probably e"ective) for tone reduction following BoNT injectionsand grade U evidence (inconclusive) for improvement in upper limb (UL) activity andfunction. BoNT injections were generally found to be safe and well tolerated with themost common side e"ect identified as a transient decrease in grip strength.
Introduction and objective
Botulinum neurotoxin (BoNT) has been used for over15 years to manage paediatric upper limb hypertonia(PULH). The goals include improvement in function,or the reduction in hypertonia facilitating ease of careand passive positioning of the arm. This paper sys-tematically reviews the evidence for BoNT use inPULH and outlines "best practice! in assessment, dos-ing, injection techniques and adjunctive interventions,based on evidence, where available, and the expertopinion of the authors to provide assistance to clini-cians managing children with PULH, as well as iden-tifying areas for future research based on gaps in theliterature.
Literature was searched and appraised using aconventional evidence hierarchy. The highest levels ofevidence available were used to develop recommenda-
tions, with randomized controlled trials (RCTs) andsystematic reviews preferentially sought. Expert opin-ions, where included, have been clearly labelled andshould be interpreted with judicious caution. Recom-mendations for research were made based on the gapsindentified in the literature. All recommendations weregraded based on the American Academy of Neurology(AAN) [1] evidence classification. The expert interna-tional team included a developmental paediatrician,occupational therapists, an orthopaedic surgeon, apaediatric neurologist and a paediatric rehabilitationspecialist.
Definition
Hypertonia is defined as "abnormally increased resis-tance to externally imposed movement about a joint![2]. In the paediatric upper limb (UL), hypertonia ismost frequently associated with spasticity, dystonia,or a combination of both hypertonia sub-types.Cerebral palsy (CP) and acquired brain injury are thetwo most common diagnoses associated with PULH[2]. In addition to hypertonia, other UL impairments
Correspondence: D. Fehlings, MD, MSc, FRCPC, Bloorview
Research Institute, Bloorview Kids Rehab, University of Toronto,
Toronto, ON, Canada (tel.: +416 425 6220, x3586;
fax: +416 424 3837 ; e-mail: [email protected]).
38! 2010 The Author(s)
Journal compilation ! 2010 EFNS
European Journal of Neurology 2010, 17 (Suppl. 2): 38–56 doi:10.1111/j.1468-1331.2010.03127.x
Freitag, 23. November 2012
European Consensus - Update 2009
Part I | tabulated evidence report
(1) cerebral palsy (2) integrated therapy(3) medico-legal and medico-economical aspects of BoNT(4) common indications(5) dosage and dose modifiers(6) safety(7) therapy and procedures(8) assessment and evaluation(9) therapy adherence(10) research challenge
Part 2 | CPGraph Treatment Modalities Gross Motor Function
Freitag, 23. November 2012
2: Integrated therapy - evidence based
1. Range of conservative and surgical strategies considering all dimensions of ICF(PT, OT, Speech, Robotics, CIMT, HABIT, orthosis, casting, splints, baclofen, other pharmacotherapy, surgery, etc….Botulinum toxin)
2. Insufficient evidence to either support or refute the use of these interventions before or after BoNT injections (Lowe K, DMCN 2006, Hagglund G, JPO (B) 2005, Molenaers G, 2006 JBJSA, Lannin DMCN 2006)
3. Robotic assisted therapy can serve as an intervention model where activity parameters can be measured during therapy intervention (Meyer-Heim, Arch Dis Child 2009, Borggraefe MovDisord 2008, Fasoli AJPMR 2008, Borggraefe, EJPRM 2010)
Freitag, 23. November 2012
Fig.1–CPGra
phtrea
tmen
tm
odalities
–gro
ssm
otorfu
nctio
n.
european
journalofpaedia
tric
neurology
14
(2010)45–66
58
CP: Integrated / Multidisciplinary Therapy
Freitag, 23. November 2012
0 1 2 3 4 5 6 7 8 9 10 11 12 13 140,5 1,5 2,5
D
D
C
C
A
C
A
A
CA
A
CheckSUR
CheckSUR CheckSUR
CheckSUR CheckSUR
CheckSUR CheckSUR
CheckSUR CheckSUR
CheckSUR CheckSUR
AA
A
B
A
C
D
D
D
D
D
DC
A
DCB
A
C
B D
A
C B
B
A
DC
B
AC
A
A
C B
B
C
B
B
B
B
B
A
C
A
C
3,5 4,5 5,5 6,5 7,5 8,5 9,5 10,5 11,5 12,5 13,5age
Ort
hopa
edic
su
rger
yIn
trat
heca
l ba
clof
enB
otul
inum
Tox
inO
ral m
edic
atio
nO
rtho
ses
/ aid
sFu
ncti
onal
th
erap
ies
TREATMENT MODALITIES - GROSS MOTOR FUNCTION
Check for surgicalintervention
D 75-100%
Percentage of children with BSCP, for whom the respective form of treatment is suitable
CPGRAPH
© F
loria
n H
ein
en
, M
un
ich
, E
ditio
n 3
/20
11
. G
MF
M-G
rap
h a
nd
GM
FC
S-I
llu
str
atio
ns b
y c
ou
rte
sy o
f P
ete
r R
ose
nb
au
m,
Ca
na
da
an
d H
. K
err
Gra
ha
m, A
ustr
alia
.
A 0-25%B 25-50%C 50-75%
GMFCS Level I
GMFCS Level II
GMFCS Level III
GMFCS Level IV
GMFCS Level V
Freitag, 23. November 2012
Botulinum neurotoxin (BoNT)
1. Anaerob gram + bacteria
2. 7 Serotypes (A-‐G)
3. Light chain / heavy chain
4. InjecCon into the targeted Cssue
5. Does not cross blood-‐brain-‐barrier
6. Not cytotoxic
7. New Terminology
- Botox: onabotulinumtoxinA
- Xeomin: incobotulinumtoxinA
- Dysport: abobotulinumtoxinA
- Neurobloc: rimabotulinumtoxinB
Freitag, 23. November 2012
BoNT - Mechanism of action
1. Local / Focal inhibition - Neuro-muscular junction- Muscle spindle - down regulation of spinal circuit- Neuro-glandular junction
2. Heavy chain: binding & internalisation
3. Light chain: inhibition of cholinergic transmission
4. Cleavage of membrane-fusion proteines
5. dose-dependent effect
Freitag, 23. November 2012
3: Medico-legal & Medico-economical aspects
1. Licenses for BoNT treatment show a great variety between countries, and are restricted to specific preparations => be familiar
2. Licensing does not reflect the clinical needs, especially for children with CP (multi-centre studies of different preparations on theway) => documentation
3. Strong level of pharmaco-vigilance is required:=> severely affected children with bilateral CP, GMFCS Levels (III–) IV-V suffering from multiple additional impairments=> careful decision-making on dosage, dilution, procedure and injection => control rests in the hands of the treating physician and has to be adapted
Freitag, 23. November 2012
4: Common indications
1. Spastic movement > dystonic movement disorders=> therapy goal defined according ICF dimensions
2. Increasing number of ‘‘focal’’ indications > multi-muscle, multi-level treatment approach (Molenaers G, Eur J Neurol 1999, Heinen MovDisord 2006) => reversibility of BoNT during motor development
3. Development of distinctive motor patterns (Rodda & Graham, Winters, Gage & Hicks) => adaptive approach to changing clinical patterns
Freitag, 23. November 2012
5: Dosage and dose modifiers
1. Different preparations => different biological activity=> dose conversion factors are NOT applicable
2. Individual dosages must be calculated independently „check & balance“- units per muscle, per injection site, per kg body weight per muscle (U/kg/muscle)- total units per kg body weight per session,- total units per treatment session
3. Dose modifiers- severity of CP- accompanying diagnoses- predominance of movement disorder (spasticity, dystonia)- activity and size of the injected muscle- dynamic versus fibrotic muscle- distribution of motor endplates- experience from previous BoNT injections
Freitag, 23. November 2012
1. ona: Powder 50 & 100 Units / Vial
2. abo: Powder 500 Units / Vial
3. inco: Powder 50 & 100 Units / Vial
4. rima: Solution 0,5 & 1 ml / Vial = 2500 & 5000 Units / Vial
=> Dilute in 1 / 2 / 4 / 5 ml / Vial = different concentrations
=> small muscles 1-2 ml / Vial=> large muscles 2-5 ml / Vial
Dosage & Dilution
Freitag, 23. November 2012
There are no dose-ranging studies that address theoptimum dose of BOTOX!. Recommendations inprevious studies, consensus statements and this docu-ment are !expert opinion"; that is to say, no RCTs havebeen published. Given recent concerns about adverseevents, the authors have chosen total doses in units perKg body weight for BOTOX!, which are intermediatebetween the figures proposed in two previous consensusstatements, and which err on the side of caution(Table 3). It is the responsibility of the treating physi-cian to carefully choose the dose they consider appro-priate for the individual case concerned.
In addition to the RCTs reviewed in detail by theauthors, review of non-RCT literature confirms markedescalation in recommended doses of BOTOX!, both inrelation to specific indications such as spastic equinus aswell as in multilevel protocols. For example, in 2000,Graham [78] made the following recommendations:maximum dose at any one site 50 Units, maximum dosein any one injection session 300 Units or 12 Units per
Kg. In 2006, Heinen [79] in a European consensusstatement reported a published total dose range up to20–24 Units per Kg for this preparation (Table 3). Itshould be noted that both of these suggested upper doselimits were determined by expert opinion, not sup-ported by clinical trial.
One Class I study exists for the use of Dysport!, andthis is only for the indication of spastic equinus [52].(Table 3).
Although the incidence of adverse events followinginjection of BoNT-A in the RCTs reviewed in thispaper and in other literature remains relatively low,systemic adverse events can include generalized weak-ness, diplopia, dysphagia, aspiration, pneumonia anddeath. This serves as a warning that systemic spread ofBoNT-A may occur in children with CP and muchfurther work is required before high-dose protocols canbe accepted as safe. Given that the major risks ofserious systemic adverse events reside in the child, itseems prudent to make recommendations based on
Table 3 Products and doses
Product
Dose U/kg body weight
Maximum Total DoseRange in literature Recommendation
BOTOX! 6–24 U/Kg
(up to 30 U/Kg used
in occasional multilevel
injections)
GMFCS I–IV without risk factors: 16–20 U/Kg
GMFCS V with risk factors: 12–16 U/Kg*
<300 U [53,57]
<400–600 U [79]
Dysport! 10–30 U/Kg 20 U/Kg [52]
(level B recommendation)
200–500 U [54] (level U
Recommendation)
<900 U [79]
Risk factors include symptoms and signs of pseudobulbar palsy, swallowing difficulties, history of aspiration and respiratory disease. When risk
factors are present, evaluate the level of risk and either further reduce the total dose or avoid using BoNT-A.
*Expert opinion.
Table 4 Favourable Response to BoNT-A and physiotherapy
Aim Expected Outcome Indication
Grade of
Recommendation
Reduction in body
structures impairment
Reduction in spasticity
and improved dynamic
ROM
Decreased involuntary over-activity of injected muscles. Observed
by a reduction in !R1 R2" difference, measured on the ASAS [36]
and MTS [18].
A
Improved selective motor
control
Improved ability to isolate and selectively control ankle
movements. Selective motor control is measured via Selective
Motor Control Scale [18].
U
Improved strength Greater strength in agonist and antagonist muscle groups,
measured via a dynamometer or the Medical Research Council
scale (graded 1–5).
U
Improved passive ROM BoNT-A in combination with casting is used to reduce contracture.
Improved passive ROM is measured via goniometry.
B
Improved functional
activity performance
Improved function and
task performance
Improvements in individualized goal performance of functional
tasks (e.g. walking, running, kicking a ball). Observed by an
increase in GMFM scores [99] and /or measured by an increase in
GAS [45].
B
Improved quality of life
and personal factors
Reduction in pain Decreased pain and spasm, measured on a Visual Analogue Scale
(VAS), COPM [100], GAS [45] WeeFIM! [43] or PEDI [44].
U
18 S. C. Love et al.
" 2010 The Author(s)Journal compilation " 2010 EFNS European Journal of Neurology 17 (Suppl. 2), 9–37
World consensus 2010 (EJN)
Freitag, 23. November 2012
allow for adaptation to reduced tone and to avoidexcessive weakness through repeated injections.
Recommendation 4
Authors suggest the following:
• Not to use conversion factors between different preparations even
amongst the same serotype [44,60]
• Consideration of the severity of the motor disorder, goal of
treatment, size of the targeted muscle and body region, neuro-
muscular junction distribution in the muscle, and previous BoNT
experience when determining dose [expert opinion, supported by
15,46,54,57]
• BoNT doses should be calculated cautiously in patients with
dysphagia and breathing problems [60]
• If the treatment is to improve function, the calculated dosage should
be distributed in a small amount of normal saline in themuscle at 1–2
injection sites depending on age/size of the child [15,18,46]
• Intervals between BoNT injections should exceed 3 months and be
extended as far as clinically justifiable whilst treating the child with
functional therapy and orthotic devices [expert opinion supported
by 61–64]
Recommendations for treatment: injectiontechnique
Proper localization of the toxin injection in the desiredmuscle is crucial for maximizing the clinical e!ects of thetoxin [42,46,65]. From animal data, we can expect dif-fusion of the toxin up to 4 cm along the longitudinal axisof the muscle from the point of injection, although nosimilar data exist for humans [54]. Di!usion crossesanatomic barriers such as fascias, as described in animals
as well as in humans [55,56]; therefore, injection tech-nique, concentration, volume per injection site [57,66]and dosage potentially have an impact on treatmentoutcome. As the injection is aimed to reach the motorend-plates, their location should be kept in mind [67].
Techniques to localize the muscle [68]
PalpationAlthough used in six studies [6,7,9,10,13,17], it has beendemonstrated in adults as well as in children that pal-pation is inadequate for muscle identification, especiallyin the forearm [69,70].
EMGElectromyography was used to control injections in theUL in children with CP in two studies. There are factorsthat might reduce accuracy and practicability of theprocedure: children with CP have a limited ability toco-operate and perform selective movements [11,71],the acoustic signal is reduced in sedated children andthe procedure is painful and can require severalattempts until correct positioning of the needle isachieved. Diagnostically, EMG (multi-channel surfacerecording) can be useful in children with dystonia toidentify muscles that are responsible for the dystonicposture or movement.
Electrical stimulationElectrical stimulation is independent of selectivevoluntary motor function, and the patient!s ability to
Table 2 Dose recommendations for muscles of the shoulder and upper extremity [48,49]
Muscle
Dose range
(U/kg BOTOX!)
Max. Dose per
muscle (U BOTOX!)
Dose range
(U/kg Dysport!)
Max. Dose per muscle
(U Dysport!)
Pectoralis major 2 50 5–10 150
Teres major 2 50 5–10 150
Triceps brachii 2–4 100 10–15 250
Biceps brachii 2–3 50 5–10 150
Brachialis 2–3 50 5–10 150
Brachioradialis 0.5–2 50 5–10 150
Flexor carpi radialis 0.5–2 50 5–10 150
Flexor carpi ulnaris 0.5–2 50 5–10 150
Pronator teres 1–2 50 5–10 150
Pronator quadratus 0.5–1 25 5 150
Flexor digitorum profundus 0.5–2 50 5–10 150
Flexor digitorum superficialis 0.5–2 50 5–10 150
Extensor digitorum communis 0.5–2 25 5 100
Flexor pollicis longus 1 25 5 100
Flexor pollicis brevis/Opponens pollicis* 0.5–1 25 5 75
Adductor pollicis 0.5–1 25 5 75
Lumbricales 0.5–1 25 5 75
Total dose per treatment session 16 U/kg 400 30 U/kg 1000
Please be aware that the recommendations for BOTOX! and Dysport! are not based on a fixed conversion ratio between the two preparations
(please refer to "Preparations, conversion factors! within the text). *Due to the proximity of the two muscles they are not listed separately.
48 D. Fehlings et al.
" 2010 The Author(s)Journal compilation " 2010 EFNS European Journal of Neurology 17 (Suppl. 2), 38–56
World consensus 2010 (EJN)
„BOTOX doses used in controlled trials have a range of 1–9 U/kg body weight per treatment session and 0.3–2 (forearm) up to 4 (upper arm) U/kg body weight per muscle.Neurobloc is not included in the table, as there is limited experience with BoNT-‐B in children with PULH.“
Freitag, 23. November 2012
European Consensus: Heinen et al. 2010
Dose / kg bodyweight up to 24 kg - then adult dosages
Dose ranges [U!Units; kg bw! kilogram body weight]a
BoNT Serotype A- Preparation BOTOX!
range [U/kg bw] 1–20 (–25)max total dose [U] 400 (–600)range max dose/site [U] 10–50
- Preparation Dysport!
range [U/kg bw] 1–20 (–25)max total dose [U] 500–1000range max dose/site [U] 50–250
- Preparation Xeomin! (adult studies suggest dosage equivalence withBotox!,160, 161 but for children this needs to be confirmed)
range [U/kg bw] not established yetmax total dose [U] not established yetmax dose/site [U] not established yet
BoNT Serotype B- Preparation Neurobloc! (mainly used as second line preparation in adultneurology in case of secondary non-response to BoNT/A)
range [U/kg bw] not establishedmax total dose [U] not establishedmax dose/site [U] not established
= ona
= abo
= inco
= rima
large muscles
small muscles
onA /incoA
3-6 U/kgBW
0.5-2 U/kgBW
aboA 10-20 U/kgBW
5-10 U/kgBW
Freitag, 23. November 2012
BoNT - Cerebral Palsy:how to decide if BoNT could work
no BoNT,
but ac-vity training
&motor control training
elevated muscle tone?
+ -‐
spas-city? (MTS, MAS)
Define personal, ADL-‐relevant goals
does spas-city interfer with these goals?
(mul--‐) fokal spas-city?
good range of mo-on?Structure: BoNT & cas-ng
or hygiene, pain, posi-oningversussurgeryTherapy goal BoNT:
Func-on & Ac-vity & Par-cipa-on (Locomo-on) Injec-onprotocol
Love et al. 2010 EJ of Neurology Vol. 17, Supplement 2
+ -‐
+ -‐
+ -‐
oralmedica-on
Freitag, 23. November 2012
clincial examinationREPEAT THE LOOP UNTIL EVERY STEP IS WITHIN THE ACCEPTED DOSE RANGE,
THEN PROCEED TO THE INJECTION PROCEDURE
DOSING-LOOP BOTULINUM TOXIN
CLINICAL EXAMINATIONWHICH MUSCLES SHOULD BE TREATED?
INJECTION PROTOCOLDOSE MUSCLE
UNITS KG BW MUSCLE
TOTAL DOSE SESSIONTOTAL DOSE KG BW* SESSION MAXIMUM UNITS MUSCLE
MAXIMUM UNITS SITE
© A
S S
ch
roe
de
r &
F H
ein
en
, V
ers
ion
2.2
011
*kg bw – kilogram bodyweight
5
4
3
1 7
2
Reduce number of muscles if neccessary
Freitag, 23. November 2012
Example injection documentation
M. ilio
psoa
s re
M. Ilio
psoa
s li
M. R
ec fe
m re
M. R
ec fe
m li
…..
13.06.12 25 4 Botox 2x50 2x50 3x25 3x25 ... 350 14
_____________________________________ 1
Freitag, 23. November 2012
6: Safety
1.! Used for over 20 years
2.! AE: focal (local, distant), generalized and procedural
3.! Safety discussion (Germany, USA, etc.)=> Germany 06/2007 – 09/2008: No evidence showing a causal
connection between the fatal outcome of five reported patients and their prior treatment with BoNT.
=> USA, FDA 01/2008 – 08/2009: boxed warnings on their labels: spread from the area of injection to other areas of the body with potentially life-threatening swallowing and breathing difficulties and even death.
4.! Cave: more severe GMFCS and /or accompanied impairments
Freitag, 23. November 2012
Abb 4: Prädiktives Risiko (incl. random intercept)
Safety 180 Patients - 616 sessions - 54 AE - 8.8 %
Predictive Risk of occurence of AE in correlation to dose / kg bodyweight
Retrospectiv versus prospective assessment of AE differs
AE rating: light: 5,0 %, moderate: 3,1 %, severe: 0,2%
Freitag, 23. November 2012
7: Therapy and procedures
1.! Repeated multiple, painful, but elective procedure
2.! The right for a pain free therapy (ethical necessity)
3.! Optimal regimen will vary between individuals & institutions:- influenced by the age of the child- the GMFCS- the number of muscles to be treated
4.! Accurate localization technique
Freitag, 23. November 2012
8: Assessment and evaluation
1. Purpose-built classification tools and standardized clinical assessments => same language => using consistent and valid instruments, matched to the dimensions of the ICF
2. SCPE, GMFCS, MACS, HIP-SURVEILLANCE
3. Clinical Examination: - Modified Ashworth Scale (MAS) - Modified Tardieu Scale (MTS)- Active / passive Range of Motion- (3-D / observational) Gait analysis (PRS)- Goal Attainment Scaling (GAS)
Evaluation vor
Injektion
Ultraschall-gesteuerte
Botulinumtoxin
Evaluation 4-6
Wochen nach BoNT
V1 V2 V3
t
Spasticity versus Contracture
Freitag, 23. November 2012
World consensus 2010: Assessment
Table 2 Recommended assessments
Tool
ICF domain Domain of measurement Properties Purpose
Body
Structures Activities Participation Spasticity Function Valid Reliable Responsive
Clinical
Practice Research
Australian Spasticity
Assessment Scale
(ASAS) [36]
• Quantifies the amount of muscle
spasticity present via measurement
of the !spastic catch" on an ordinal
scale
• • ? • •
Modified Tardieu Scale
(MTS) [18]
• Quantifies the degree of muscle
spasticity present via measurement
of the !spastic catch" to determine
muscles for injection (continuous
scale in degrees)
? ? ? • •
Muscle length as
measured by range of
joint motion (ROM)
• Measure the muscle length to
understand the degree of
contracture present (represented in
degrees of joint movement)
• • • • •
Goal Attainment Scaling
(GAS) [45]
• • • Measures intervention outcomes
based on individualised goals
• • • • •
Video Gait Analysis
(VGA or 2DGA)
• Records sagittal and frontal gait
parameters
? • • • •
3DGA • • Primarily EMG Kinetic and kinematic data • • • •Physician Rating Scale
(PRS) [38]
• Ordinal criteria descriptors of gait
quality
? • • •
Functional Independence
Measure for Children
(WeeFIM!) [43]
• Evaluation, self-care independence of
children
• • ? •
Pediatric Evaluation of
Disability
Inventory(PEDI) [41]
• Evaluation, self care, mobility and
social function of children with
physical disability
• • • •
Gross Motor Function
Measure (GMFM-66)
[44]
• Evaluation, determination of gross
motor capacity
• • • •
• Addresses this domain/possesses this property/fulfills this purpose; ?: may possess this property.
12S.C.Love
etal.
"2010TheAuthor(s)
Journalcompilatio
n"
2010EFNSEuropeanJo
urnalofNeurology17(Suppl.2),9–3
7
Love et al. 2010 EJ of Neurology Vol. 17, Supplement 2Freitag, 23. November 2012
Example patients - select assessment tools
1. BSCPGMFCS Level 2,4 years of age
- mod. Tardieu Scale- a/p ROM- Video Gait doc.- GAS- X-Ray hip
2. Dyskinetic CPGMFCS Level 516 years of age
- Positioning- Pain- CPCHILD- X-Ray hip & spine- autonomic function- GAS
3. USCP right sideGMFCS Level 16 years of age
- MACS level- AHA-Test- a/p ROM- mod. Tardieu Scale (large joints)- GAS
Freitag, 23. November 2012
World consensus: BoNT/A evaluation of effectiveness
adductors and hamstrings combined with use of thestanding, walking and sitting hip (SWASH) bracecompared with !standard" management (Appendix 1).Whilst children in the treatment group progressed tosurgery at a significantly lower rate than those in thecontrol group (possibly influenced by the rate ofprogression of contractures), the authors concludedthis was not an e!ective way to manage hip displace-ment in the long term. Moreover, a significant numberof adverse events were reported in the BoNT-A group,and, in a previous subgroup analysis, no significantimprovement in GMFM was found.
In summary, taking into consideration the class ofthe study and the direction of the change in outcomemeasure, there is a Grade A recommendation thatBoNT-A injections to the adductors and hamstrings isnot effective to improve gross motor function in chil-dren with CP, as determined by GMFM. There is aGrade A recommendation that BoNT-A injections areeffective in delaying the need for surgery in the man-agement of hip displacement in children with CP, butonly in the short term. There is a level C recommen-dation that BoNT-A injections are possibly e!ective inchildren achieving intervention goals as determined bythe GAS.
Group 5 RCTs: multilevel BoNT-A injections to
improve gait and functioning. N = 6
The RCTs in this group were even more heterogeneousin terms of study populations, quality of RCT, injectionprotocols and outcome measures than the previouslyreported groups [72–77].
Of the six RCTs identified, the authors graded fouras Class II and two as Class III, with no studiesreaching a Class I grading (Appendix 1). The studiesreported widely di!erent outcome measures, with thestudy by Scholtes et al., although included twice,presumably reports the same patient cohort. The 2006study by Scholtes [74] reports gross motor outcomes,and the 2007 study [75] reports spasticity, musclelength and gait outcomes. In this group, only onestudy reports the following outcomes: Vulpe Assess-ment Battery (VAB) [72], GAS [4], 3DGA [75] andPEDI [77]. In contrast, four studies reported outcomesin terms of gross motor function, principally using theGMFM [72,74,76,77]. However, the changes in grossmotor function were contradictory, with two studies[72,77] finding no significant improvement in grossmotor function and two studies [74,76] reporting asmall improvement. Therefore, the classification ofrecommendation for multilevel injections is graded aslevel U. That is to say, current data are inadequate orconflicting.
Comparisons of the studies reporting variable chan-ges in gross motor function in children with CP showconsiderable variation in age and GMFCS levels.Studies reporting younger children at GMFCS levels Iand II have found more consistent improvements ingross motor function. In those studies investigatingchanges in gross motor function in older children and atGMFCS levels III and IV, either less improvement orno improvement in gross motor function is generallyreported. In older children with more physical limita-tions, there may be less potential to show improvementin gross motor function, and the presence of occultcontractures may also be an important factor indecreasing the benefits of BoNT-A injection.
Recommendation 3
• BoNT-A is established as effective in the management of spastic
equinus to improve gait. (level A)
• BoNT-A is probably effective to improve goal attainment and
function in the management of spastic equinus (level B)
• BoNT-A is similar to serial casting in the management of spastic
equinus with current data being inadequate or conflicting (level U)
• BoNT-A injections to the adductor muscles is probably effective in
some specific areas of goal attainment (level B)
• BoNT-A injections to the adductor muscles do not improve gross
motor function (level A)
• BoNT-Ainjections to theadductor (andhamstring)musclesmaydelay
hip displacement, but does not affect long-term outcome (level A)
• BoNT-A injections to multiple lower limb muscles have inadequate
and conflicting data in respect of gait, goal attainment and function
(level U)
Injection protocols, dose, dilution andinjection sites
Given the widespread use of BoNT-A therapy in chil-dren with CP, the multiple indications and heteroge-neous groupings of target muscles, it is unsurprisingthat the evidence base for promoting safety and e"cacyremains very limited, and much of the current clinicaluse of BoNT-A in children with CP remains !o! label".
Two commercially available BoNT-A preparationsare regularly used in children with CP: BOTOX!
(Allergan Pty Ltd) and Dysport! (Ipsen). There is verylittle published information on the use the Xeomin!
(Merz Pharmaceuticals) BoNT-A product, which waslaunched in 2005. Each preparation has a unique bio-logical potency, and there are no firmly establishedconversion factors. It is important for clinicians to beaware that the doses for these products are not inter-changeable. We strongly advise against the use ofconversion factors between di!erent preparations onBoNT-A.
BoNT-A consensus statement: PLL 17
" 2010 The Author(s)Journal compilation " 2010 EFNS European Journal of Neurology 17 (Suppl. 2), 9–37
Love et al. 2010 EJ of Neurology Vol. 17, Supplement 2Freitag, 23. November 2012
Conclusion Consensus
European Journal of Neurology (2010) Vol. 17, Supplement 2
• It is recommended that BoNT treatment for spastic-ity is used as part of an integrated multidisciplinaryrehabilitation programme to optimise the likelihoodof treatment goals being achieved.
• BoNT should be used to address clearly identifiedproblems resulting from muscle over-activity con-fined to one or a group of muscles that contribute toa specific functional deficit.
• BoNT will not necessarily recover lost function, butmay improve functional outcomes by allowing rangeof motion to be regained, reducing pain and restoringmore balanced muscle function, leading to improve-ment in movement control.
• BoNT treats muscle over-activity, while targetedtherapy treats muscle under-activity; consequently,BoNT treatment is usually an adjunct to therapyrather than the other way round.
What is the effectiveness of BoNT treatmentfor children and adults with neurologicalimpairments?
A summary of the scientific evidence for the e!ective-ness of BoNT treatment in children and adults withneurological impairments is provided (Table 2).Detailed appraisal of this evidence is contained withinthe seven specialty International Consensus Statementsin this supplement.
Conclusion
BoNT is now an established safe and e!ective treatmentfor many indications in children and adults with neu-rological impairments. There is good quality scientificevidence to support the e"cacy of BoNT to reducemuscle over-activity in the limbs secondary to centralnervous system disorders in adults and children, toaddress primary or secondary cervical dystonia, toreduce saliva flow and to treat some pain syndromes.There is emergent evidence for the e"cacy of BoNT toreduce other types of pain, including neuropathic pain,to ameliorate focal tremor and also to improve func-tion, following treatment of focal muscle over-activity.
Acknowledgements
The Cerebral Palsy Institute would like to sincerelythank the Principal Authors involved in the develop-ment and leadership of these International ConsensusStatements, including: Professor H. Kerr Graham;Professor John Olver; Associate Professor Victor S.C.Fung; Associate Professor Barry Rawicki; Dr BarbaraJ. Singer and Dr Iona Novak. Sincere thanks are alsoextended to the Sub-Committee Chairs: AssociateProfessor Darcy Fehlings; Associate Professor Sarah C.Love; Professor Geo! Sheean and Associate ProfessorDinah Reddihough.
Table 2 Effectiveness of BoNT for children and adults with neurological impairments
Treatment outcomes from
intra-muscular injections
Adults Children
Lower limb
hypertonicity
Upper limb
hypertonicity
Neck region
hypertonicity
Lower limb
hypertonicity
Upper limb
hypertonicity
Neck region
hypertonicity
Reduced spastic
muscle over-activity
A
Established
effective
A
Established
effective
U
Inconclusive
A
Established
effective
B
Probably effective
U
Inconclusive
Reduced dystonic
muscle over-activity
Ua
Inconclusive
Ua
Inconclusive
A
Established
effective
Not reviewed Ba
Probably effective
Ua
Inconclusive
Increased range
of motion
U
Inconclusive
U
Inconclusive
B
Probably effective
B
Probably effective
U
Inconclusive
U
Inconclusive
Increased gross
motor function
U
Inconclusive
d d B
Probably effective
d d
Increased goal
achievement
B
Probably effective
U
Inconclusive
B
Probably effective
B
Probably effective
A
Established effective
U
Inconclusive
Reduced pain U
Inconclusive
U
Inconclusive
B
Probably effective
U
Inconclusive
U
Inconclusive
U
Inconclusive
Treatment outcomes from intra-glandular injections Adults Children
Reduced saliva secretion A
Established effective
A
Established effective
aLack of sensitive outcome measures & difficulty in assembling homogenous groups for clinical trials affect this finding.
A, established effective; B, probably effective; U, inconclusive; d, not appropriate
6 A. Esquenazi et al.
! 2010 The Author(s)Journal compilation ! 2010 EFNS European Journal of Neurology 17 (Suppl. 2), 1–8
Freitag, 23. November 2012
This systematic review found high level evidence supporting the use of BoNT-A as an adjunct to managing the upper limb in children with spastic CP.
BoNT-A should not be used in isolation but should be accompanied by planned occupational therapy.
Further research is essential to identify children most likely to respond to BoNT-A injections, monitor longitudinal outcomes, determine timing and effect of repeated injections and the most effective dosage, dilution and volume schedules.
The most effective adjunct therapies including frequency and intensity of delivery also requires investigation.
[Intervention Review]
Botulinum toxin A as an adjunct to treatment in themanagement of the upper limb in children with spasticcerebral palsy (UPDATE)
Brian J Hoare1, Margaret A Wallen2, Christine Imms3, Elmer Villanueva4, Hyam Barry Rawicki5, Leeanne Carey6
1School of Occupational Therapy, La Trobe University, Victorian Paediatric Rehabilitation Service, Monash Medical Centre, Clayton,Australia. 2Occupational Therapy, The Children’s Hospital at Westmead, Westmead, Australia. 3School of Occupational Therapy,LaTrobe University, Murdoch Children’s Research Institute, Royal Children’s Hosptial, Melbourne, Australia. 4Gippsland MedicalSchool, Monash University, Churchill, Australia. 5Victorian Paediatric Rehabilitation Service, Monash Medical Centre, Clayton,Australia. 6Division of Neurorehabilitation and Recovery, National Stroke Research Institute, Florey Neuroscience Institutes and,School of Occupational Therapy, LaTrobe University, Melbourne, Australia
Contact address: Brian J Hoare, School of Occupational Therapy, La Trobe University, Victorian Paediatric Rehabilita-tion Service, Monash Medical Centre, 246 Clayton Road, Clayton, Victoria, 3086, Australia. [email protected]@southernhealth.org.au.
Editorial group: Cochrane Movement Disorders Group.Publication status and date: New search for studies and content updated (conclusions changed), comment added to review, publishedin Issue 1, 2010.Review content assessed as up-to-date: 17 August 2008.
Citation: Hoare BJ, Wallen MA, Imms C, Villanueva E, Rawicki HB, Carey L. Botulinum toxin A as an adjunct to treatment in themanagement of the upper limb in children with spastic cerebral palsy (UPDATE). Cochrane Database of Systematic Reviews 2010, Issue1. Art. No.: CD003469. DOI: 10.1002/14651858.CD003469.pub4.
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
A B S T R A C T
Background
Cerebral palsy (CP) is “a group of permanent disorders of the development of movement and posture causing activity limitation(s) thatare attributed to non-progressive disturbance that occurred in the developing fetal or infant brain” (Rosenbaum 2007, p.9). The spasticmotor type is the most common form of CP. Therapeutic management may include splinting/casting, passive stretching, facilitationof posture/movement, spasticity-reducing medication and surgery. Botulinum toxin-A (BoNT-A) is now used as an adjunct to thesetechniques in an attempt to reduce spasticity, improve range of movement and function.
Objectives
To assess the effectiveness of injections of BoNT-A or BoNT-A and occupational therapy in the treatment of the upper limb in childrenwith CP.
Search methods
We searched the Cochrane Controlled Trials Register/CENTRAL (The Cochrane Library, Issue 3, 2008), MEDLINE (1966 to AugustWeek 1 2008), EMBASE (1980 to 2008 Week 28) and CINAHL (1982 to August Week 1 2008).
Selection criteria
All randomised controlled trials (RCTs) comparing BoNT-A injection or BoNT-A injection and occupational therapy in the upperlimb(s) with other types of treatment (including no treatment or placebo) in children with CP.
1Botulinum toxin A as an adjunct to treatment in the management of the upper limb in children with spastic cerebral palsy (UPDATE)
(Review)
Copyright © 2010 The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.
Freitag, 23. November 2012
Thank you very much
Paediatric NeurologyHauner Children‘s Hospital, Munich, Germany:
Helene AuffermannIngo BorggraefeRosemarie GeenenMaesa Al-‐HallakFlorian HeinenMaria HomburgKrisCna HußAnita Laage GauppAlexandra SitzbergerKatharina VillBirgit WarkenMaren Jawad
Integrated Center for Research and Treatment of Ver-go, Balance and Ocular Motor Disorders, IFBLMU,: Munich, Germany:Verena BruemmerKlaus JahnThyra LanghagenThomas Stephan
Dep. of Clincial Radiology, Munich, Germany:Birgit Ertl-‐WagnerInga KoerteDenise Steffinger
Paediatric NeurologyRehabilita-ons Centre, Vogtareuth:
Steffen BerweckChrisCne Janssen
Clinic of Physical Medicine and Rehabilita-on, Munich, Germany:
Josef IlmbergerCornelia Schlick
Bregenz, Austria:Kurt Schlachter
Trondheim, Oslo, Norway:Guro AndersenAreej ElkamilTorstein Vic
Perth, Australia:Catherine ElliotSiobhan ReidJane ValenCne
NIH, Washington, USA:Katharine Alter Siddhartha Sikdar
Freitag, 23. November 2012